This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The most common neurological complication of NF1 in childhood is cognitive deficits for which there are not effective specific pharmacological treatments. Studies indicate that LovastatinTM can reverse the biochemical, electrophysiological and cognitive deficits observe in Nf1 +/- mice to levels comparable to wild-type control mice. Nf1+/- mice treated with LovastatinTM demonstrated improved performance on tasks of spatial learning and memory (as measured by the Morris Water maze), attention, and pre-pulse inhibition. These tasks are hypothesized to reflect the cognitive deficits observed in children with NF1. The Morris Water Maze involves mechanisms of learning and memory, which relies on hippocampal functioning. While visual-spatial deficits have been reported in children with NF1 (e.g. Skirmisher, Billingsley, Slopes &Moore, 2003), no studies have reported on the visual spatial learning abilities in this cohort. LovastatinTM, which targets the inhibition of ras, is a logical choice as a potential therapeutic intervention for children with NF1 and cognitive deficits. Clinical trials indicate that LovastatinTM is effective and safe to treat heFH in adults and children. Results from a recently completed Phase I trial indicate that LovastatinTM is safe to be used in children (10-17 years) with NF1 (Acosta et al., 2007). Currently, no studies have examined the effect of LovastatinTM on cognitive functioning in individuals with NF1. This study will determine the efficacy of LovastatinTM as a treatment for the cognitive defects observed in children with NF1. We will conduct a multi-centre randomized, double-blind, Phase II trial with two treatment arms (LovastatinTM/placebo) for 16 weeks. Based on predictions from the NF1 murine mouse model, it is expected that children with NF1, who are impaired on a visual spatial learning task and/or an attention task, will benefit from LovastatinTM.